Resolution of racemic compounds is becoming an increasingly important industrial function for the last several years. This is because the resolved compounds, the optically active D or L isomers, have valuable utility and applications in fields such as drugs, fragrances, electronics and the like. Particularly in the pharmaceutical field there is a great interest in optically active isomeric forms of drugs. See for example Chiral Drugs, S. C. Stinson, Chemical and Engineering News, American Chemical Society, Washington, D.C., 44 (Oct. 9, 1995); idem, ibid., 38 (Sep. 27, 1993); and Chiral Drugs fast entering the Mainstream, Chemical Marketing Reporter, 5 (Jun. 10, 1996).
Obtaining optically active (chiral) isomeric forms of compounds has been traditionally achieved by processes such as chiral synthesis, asymmetric hydrogenation of appropriate precursors, enzymatic resolution, chromatic processes, and the like. However, such traditionally available synthetic methods to resolve racemates generally involve complicated or selective chemical reactions which necessitate a subsequent reverse reaction to yield the desired enantiomer; many of them are expensive and the yields are not always satisfactory. The enzymatic processes are generally slow. Since most chemical reactions result in the formation of racemates, an economical approach to resolving such readily available racemates would be the cheapest and easiest way to obtain chiral isomers.
Pasteur discovered the property of optical activity displayed by chiral compounds, the resolution of racemic mixtures into their enantiomeric components has posed a challenge. Substantial progress in separating enantiomeric pairs has been achieved since Pasteur's laborious hand separation method of the enantiomeric crystals of racemic sodium ammonium tartarate.
A traditional method of resolution comprises by reacting a racemic mixture with a second optically active substance to form a pair of diastereoisomeric derivatives. Such derivatives generally have different physical properties which permit their separation by conventional means. For example, fractional crystallization often permits substantial separation to afford at least one of the diastereoisomer in a pure state. An appropriate chemical transformation then converts the purified derivative, which was formed initially solely to prepare a diastereomeric pair, into one enantiomer of the originally racemic compound. Such traditional methods suffer from many limitations. Generally, only one of the enantiomeric pairs can be obtained, so yields are necessarily less than 50%. The separation of materials so obtained usually is not completed; leading to materials with enhanced rather that complete optical activity. The optically active materials used for the diastereoisomers frequently are expensive, toxic and partially recoverable.
Article titled “Chiral separation of binaphthol enantiomers on molecularly imprinted polymer monolith by capillary electro-chromatography” by Z S Liu et al. published in Anal Sci. 2004 April; 20(4):673-8 reports a novel enantioseparation monolithic stationary phase for binaphthol based on a molecular imprinting method was introduced and evaluated in capillary electrochromatography (CEC). The monolithic stationary was prepared by the in situ copolymerization of methacrylic acid and ethylene dimethacrylate in a porogenic solvent (toluene or toluene-isooctane) in the presence of an imprinting molecule, (R)-1,1′-bi-2,2′-naphthol. Such stationary phases could separate the enantiomers of binaphthol. The influence of the polymerization condition and the electrochromatographic parameters on the enantiomer separation was also studied. Initial studies showed that a higher molecular ratio of the imprinted molecule to the functional monomer, a higher content of porogen, a higher content of acetonitrile, a higher pH, as well as the addition of Tween 20, gave higher enantiomer selectivity.
Article titled “Tartaric acid derivatives as chiral selectors in liquid chromatography” by E. Heldin et al. published in Chromatographia, November 1991, 32 (9-10), pp 407-416 reports direct separation of enantiomeric amino-alcohols using tartaric acid derivatives as chiral complexing agents in organic stationary or mobile phases is described. Among the tartaric acid derivatives studied, only tartrates having hydroxyl groups attached to the asymmetric carbon atoms (C2) and (C3) free, gave enantioselective retention for epherrine stereoisomers. (2R, 3R)-di-n-butyl tartrate (DBT) dissolved in n-hexane as stationary liquid phase gave higher stereoselectivity than DBT in dichloromethane. Both hydrophilic (Nucleosil CN) and hydrophobic (porous graphitic carbon) solid supports were found to affect the retention and enantioselectivity when using a chiral liquid stationary phase.
PCT Patent application No. WO1996011894 discloses a process for separating enantiomers from a racemic mixture by countercurrent extraction using at least two substances, one of them a liquid in which the racemic mixture to be separated is present, the other containing a chiral adjuvant which is combined with or part of a gel forming substance in the form of discrete particles in a liquid separated from the counter currently flowing liquid containing the racemate to be separated by a microporous membrane having a pore size such that the pores can no longer be penetrated by the gel forming particles separated on conclusion of the extraction, followed by the setting free therefrom of one of the enantiomers under the influence of a stimulus, after which the particles are re-incorporated into the extracting process if so desired.
E.P. Patent No. 656919 discloses MMA-DVB copolymers suitable for use in making polymeric adsorbents for ion-exchange resins. Novel porous copolymers are disclosed which can be used to prepare ion-exchange resins and polymeric adsorbents. The copolymers comprise a copolymer of at least one monovinylidene monomer and a crosslinking monomer and have a unique cellular pore structure. The cellular structure comprises a macroporous void phase which is dispersed within a continuous copolymer phase.
U.S. Pat. No. 5,461,175 discloses a method for separating enantiomers of derivatives of aryloxipropanolamines is disclosed. In the method, the derivative is contacted with a chiral solid-phase chromatography material containing molecular imprints of an optically pure enantiomer of the derivative to be separated. A chiral solid-phase chromatography material for use in the method is also disclosed. This material consists of a polymer prepared by polymerization of a monomer in the presence of a crosslinking agent and of an optically pure enantiomer of the derivative to be separated, a molecular imprint of the optically pure enantiomer being formed in the polymer by non-covalent interactions between the monomer and the optically pure enantiomer. Moreover, the invention disclosed the use of the molecular imprinting method for preparing a chiral solid-phase chromatography material for use in the method.
U.S. Pat. No. 6,709,597 discloses a process for the separation of racemic mixtures comprising development of a denser molecular imprint on silica with a desired enantiomer by sol-gel protocol. More particularly, nanoporous silica with a defined shape and size is developed by molecular imprinting of the desired enantiomer for the resolution of corresponding racemic mixture.
U.S. Pat. No. 5,994,560 discloses a novel process to resolve a racemic compound into its optically active isomers without need for chemical transformation such as salt formation. The process advantageously utilizes polymers containing chiral moieties in their repeat units as well as exhibiting critical solution temperature behavior in a suitable solvent.
The literature survey shows that the chiral component was introduced in polymer backbone directly by adding as co-monomer, due to this direct insertion in to polymer backbone most of the chiral functional groups were buried, resulting lower enantiomeric excess separation. It is, therefore, an object of this invention to provide a viable process to resolve racemates into optically isomers.